Method for data reduction and calibration of an oct-based physiological monitor

ABSTRACT

The present invention relates to a method and system for estimating blood analyte levels using a noninvasive optical coherence tomography (OCT) based physiological monitor. An algorithm correlates OCT-based estimated blood analyte data with actual blood analyte data determined by other methods, such as invasively. OCT-based data is fit to the obtained blood analyte measurements to achieve the best correlation. Once the algorithm has generated sets of estimated blood analyte levels, it may refine the number of sets by applying one or more mathematical filters. The OCT-based physiological monitor can be calibrated using an Intensity Difference plot or the Pearson Product Moment Correlation method.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of pending U.S. application Ser. No.11/403,635 filed on Apr. 13, 2006, which claims the benefit under 35U.S.C. §119(e) of U.S. Provisional Applications Ser. Nos. 60/671,007filed Apr. 13, 2005 and 60/671,285 filed Apr. 14, 2005, and which is acontinuation-in-part of U.S. application Ser. No. 10/916,236 filed onAug. 11, 2004, now U.S. Pat. No. 7,254,429, each of which isincorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to a method for estimating blood glucoselevels using a noninvasive optical coherence tomography (OCT) basedblood glucose monitor.

BACKGROUND OF THE DISCLOSURE

Monitoring of blood glucose (i.e., blood sugar) levels has long beencritical to the treatment of diabetes in humans. Current blood glucosemonitors involve a chemical reaction between blood serum and a teststrip, requiring an invasive extraction of blood via a lancet orpinprick to the finger. Small handheld monitors have been developed toenable a patient to perform this procedure anywhere, at any time. Theinconvenience associated with this procedure—specifically, the bloodextraction and the need for test strips—has led to a low level ofcompliance by diabetic patients. Such low compliance can lead todiabetic complications. Thus, a non-invasive method for monitoring bloodglucose is needed.

Studies have shown that optical methods can be used to detect smallchanges in light scattering from biological tissue related to changes inlevels of blood sugar. Although highly complex, a first orderapproximation of the relationship of the intensity of monochromaticlight reflected by biological tissue can be described by the followingsimplified equation:

I _(R) =I _(O)exp[−(μ_(a)+μ_(s))L],

where I_(R) is the intensity of light reflected from the skin, I_(O) isthe intensity of the light illuminating the skin, μ_(a) is theabsorption coefficient of the skin at the specific wavelength of thelight, μ_(s) is the scattering coefficient of the skin at the specificwavelength of the light, and L is the total path traversed by the light.From this relationship it can be seen that the intensity of the lightreflected from the skin decays exponentially as either the absorption orthe scattering by the tissue increases.

It is well established that there is a difference in the index ofrefraction between blood serum/interstitial fluid (IF) and cellmembranes (such as, membranes of blood cells and skin cells). (See, R.C. Weast, ed., CRC Handbook of Chemistry and Physics, 70th ed. (CRCCleveland, Ohio 1989.)) This difference can produce characteristicscattering of transmitted light. Glucose, in its varying forms, is amajor constituent of blood and IF. The variation in glucose levels ineither blood or IF changes its refractive index and thus, thecharacteristic scattering from blood-perfused tissue. In thenear-infrared (NIR) wavelength range (i.e., wherein the centerwavelength of the optical source is about 770 nm to about 1400 nm),blood glucose changes the scattering coefficient of the light, pi, morethan it changes the absorption coefficient of the light, μ_(a). Thus,the optical scattering of the blood/IF and cell combination varies asthe blood glucose level changes. Accordingly, there is the potential fornon-invasive measurement of blood glucose levels.

Non-invasive optical techniques being explored for blood glucoseapplications include polarimetry, Raman spectroscopy, near-infraredabsorption, scattering spectroscopy, photoacoustics, and optoacoustics.Despite significant efforts, these techniques have shortcomings, such aslow sensitivity, low accuracy (less than that of current invasive homemonitors), and insufficient specificity of glucose level measurementwithin the relevant physiological range of about 4 mM/L to about 30 mM/Lor about 72 to about 540 (mg/dL). Accordingly, there is a need for amethod to conveniently, accurately, and non-invasively monitor glucoselevels in blood.

Optical coherence tomography, or OCT, is an optical imaging techniquethat uses light waves to produce high-resolution imagery of biologicaltissue. OCT produces images by interferometrically scanning, in depth, alinear succession of spots and measuring absorption and/or scattering atdifferent depths at each successive spot. The data then is processed topresent an image of the linear cross section. Although it has beenproposed that OCT might be useful in measuring blood glucose, adifficulty associated with this technique is identifying whichportion(s) of a patient's OCT signal closely correlate(s) with apatient's blood glucose level and then calibrating a change of theidentified OCT signal portion(s) to a change in the patient's bloodglucose level, so that the changes in a patient's OCT signal may be usedto predict changes in the patient's blood glucose level. However, amethod now has been found that maximizes the correlation between the OCTsignal from a patient's skin and the patient's blood glucose levels,thereby providing a means for calibrating a device, such as an OCT-basedblood glucose monitor, for non-invasive, accurate and sensitiveprediction of the patient's blood glucose level. The present disclosureis directed to this method and other related unmet needs.

SUMMARY OF THE DISCLOSURE

The present disclosure provides a noninvasive method of determiningestimated blood glucose levels in a biological tissue of a subject usingan optical coherence tomography -based blood glucose monitor comprisinga sensor and at least one algorithm, the method comprising the steps:(a) selecting a wavelength of light for which μ_(a), an absorptioncoefficient of the biological tissue, is small relative to μ_(s), ascattering efficient of the tissue for the selected wavelength of light;(b) continuously scanning a two-dimensional surface area of thebiological tissue and interferometrically scanning the two-dimensionalsurface area of the biological tissue in a depth dimension with thelight during a time period; (c) averaging the data obtained byinterferometrically scanning the two-dimensional surface area of thebiological tissue in a depth dimension with the light to generate amultitude of optical coherence tomography scan data lines in the timeperiod, wherein the x-axis of each optical coherence tomography scandata line is depth and the y-axis of each optical coherence tomographyscan data lines is intensity; (d) calibrating the optical coherencetomography-based sensor against at least two invasively obtained bloodglucose measurements taken during the time period; and (e) allowing thecalibrated optical coherence tomography-based sensor and the at leastone algorithm to determine an estimated blood glucose level in thebiological tissue. In one embodiment, the wavelength of light in step(a) of the method is within the range of about 770 nm to about 1400 nm.In another embodiment, calibrating step (c) of the method furthercomprising the steps (i) generating a calibration set of estimated bloodglucose values; and (ii) applying the calibration set to calibrate theoptical coherence tomography-based blood glucose monitor. In anotherembodiment, in step (c) of the method, the optical coherencetomography-based blood glucose monitor is calibrated by a programmablecomputer. In another embodiment, substep (i) of calibrating step (c) ofthe method further comprises the steps: (a) selecting at least twoinvasively obtained blood glucose measurements obtained over a timeperiod, wherein the at least two measurements are spaced apart by aconcentration value of at least about 40 mg/dL; (b) selecting twooptical coherence tomography scan data lines, each scan data line havingbeen obtained on or about the time period; (c) computing intensitydifferences between the two selected optical coherence tomography scandata lines by subtracting a first baseline scan data line (n) from asecond, subsequent optical coherence tomography scan data line (n+1) atevery point along the two selected optical coherence tomography scandata lines to generate an intensity difference plot; and (d) using theintensity difference plot to determine a multitude of offsets and amultitude of intervals to construct a glucose vector grid comprising amultitude of offset, interval pairs. In another embodiment, the glucosevector grid in step (d) of the method further comprises a percentagechange value corresponding to each offset, interval pair. In anotherembodiment, wherein the method to obtain the percentage change value foreach offset, interval pair comprises the steps: (i) calculating a firstslope value for a line segment from the first baseline scan data lineand a second slope value for a line segment from the second, subsequentoptical coherence tomography scan data line for each potential offsetand interval pair; and (ii) calculating the difference between the firstslope value and the second slope value for each potential offset andinterval pair to obtain a percentage change value for each potentialoffset and interval pair.

In another embodiment, the method further comprises the steps: (e)determining a scattering coefficient proportional to a slope of eachoptical coherence tomography scan data line for each potential offset,interval pair; (f) creating a calibration curve correlating scatteringcoefficients and blood glucose values by performing a regressionanalysis, wherein each x-value comprises a scattering coefficientcorresponding to the scattering coefficient of an invasively obtainedblood glucose measurement and each y-value comprises the blood glucosevalue measured from each invasively obtained blood glucose measurement;(g) calculating a set of estimated blood glucose values from thescattering coefficients for each potential offset, interval pair; (h)refining the set of estimated blood glucose values; (i) averaging thesets of estimated blood glucose values for each point in time togenerate the calibration set; and (j) applying the calibrated sensorcomprising the calibration set and selected offset, interval pairs toall subsequent optical coherence tomography scans. In anotherembodiment, step (d) of the method further comprises the steps (i)identifying at least one data point in the intensity difference plotwhere intensity is 0, at least one data point having a maximum intensitysurrounding the at least one data point where intensity is 0, and atleast one data point having a minimum intensity surrounding the at leastone data point where intensity is 0; and (ii) identifying a potentialoffset range, wherein a first boundary of the potential offset range isthe at least one data point having a maximum intensity surrounding theat least one data point where intensity is 0 and a second boundary ofthe potential offset range is the at least one data point having aminimum intensity surrounding the at least one data point whereintensity is 0. In another embodiment, wherein the time period includesa blood glucose altering event. In another embodiment, the blood glucosealtering event is administering insulin. In another embodiment, theblood glucose altering event is eating a meal. In another embodiment,the blood glucose altering event is drinking a beverage containingsugar.

In another embodiment, refining step (h) of the method further comprisesthe step applying at least one statistical filter. In anotherembodiment, the statistical filter refines a set of average estimatedblood glucose values from each potential offset, interval pair byignoring sets of estimated blood glucose values that are outside onestandard deviation of the set of average estimated blood glucose valuesat any point in time. In another embodiment, the statistical filterrefines a set of median estimated blood glucose values by ignoring setsof estimated blood glucose values that are outside one standarddeviation of the set of median estimated blood glucose values at anypoint in time. In another embodiment, prior to generating thecalibration set of estimated blood glucose values, the at least onestatistical filter eliminates negative estimated blood glucose values.In another embodiment, prior to generating the calibration set ofestimated blood glucose values, the at least one statistical filtereliminates estimated blood glucose values of less than about 10 mg/dL.In another embodiment, prior to generating the calibration set ofestimated blood glucose values, the at least one statistical filtereliminates high estimated blood glucose values. In another embodiment,prior to generating the calibration set of estimated blood glucosevalues, the at least one statistical filter operates in accordance withequation (1). In another embodiment, prior to generating a calibrationset of estimated blood glucose values, the at least one statisticalfilter operates in accordance with equation (2).

In another embodiment, the method further comprising the steps (e)enhancing at least one discontinuity in each selected optical coherencetomography scan data line; and (f) using the at least one discontinuityto generate the potential offsets of the multitude of offset, intervalpairs. In another embodiment, step (e) of the method further comprisingthe step: generating a second derivative plot of the optical coherencetomography scan data line. In another embodiment, the method furthercomprises the step of identifying potential offsets by using the atleast one discontinuity. In another embodiment, the at least onediscontinuity indicates potential offsets that correlate closely tolocations of a tissue interface transition. In another embodiment, thetissue interface transition is a blood vessel. In another embodiment,the discontinuity corresponds to changes in blood glucose levels.

In another embodiment, calibration step (c) of the method furthercomprises the steps: (i) using a Pearson's plot to calibrate the opticalcoherence tomography-based sensor against at least two invasivelyobtained blood glucose measurements taken during the time period; and(ii) using Pearson's correlation to maximize the correlation betweendata received from the optical coherence tomography-based glucosemonitor and the invasively obtained glucose measurements. In anotherembodiment, the Pearson's plot in step (i) requires at least seven bloodglucose measurements invasively obtained over the time period.

The present disclosure further provides a noninvasive method ofproviding an estimated blood glucose level to a subject in need thereof,the method comprising the steps of: (a) identifying a subject in needthereof, (b) calibrating an optical coherence tomography blood glucosemonitor comprising a sensor and at least one algorithm against at leasttwo invasively obtained blood glucose measurements taken during a timeperiod; (c) identifying a biological tissue of the subject to be scannedby the calibrated optical coherence tomography blood glucose monitor;(d) continuously scanning a two-dimensional surface area of thebiological tissue and interferometrically scanning the two-dimensionalsurface area of the biological tissue in a depth dimension with thelight during the time period; (e) averaging the data obtained byinterferometrically scanning the two-dimensional surface area of thebiological tissue in a depth dimension with the light to generate amultitude of optical coherence tomography scan data lines in the timeperiod, wherein the x-axis of each optical coherence tomography scandata line is depth and the y-axis of each optical coherence tomographyscan data lines is intensity; and (f) allowing the at least onealgorithm to determining the estimated blood glucose level in thebiological tissue from the multitude of optical coherence tomographyscan data lines. In one embodiment, calibrating step (b) of the methodfurther comprises the steps (i) generating a calibration set ofestimated blood glucose values; and (ii) applying the calibration set tocalibrate the optical coherence tomography-based blood glucose monitor.In another embodiment, in step (b) of the method, the optical coherencetomography-based blood glucose monitor is calibrated by a programmablecomputer. In another embodiment, In another embodiment, substep (i) ofcalibrating step (c) of the method further comprises the steps: (a)selecting at least two invasively obtained blood glucose measurementsobtained over a time period, wherein the at least two measurements arespaced apart by a concentration value of at least about 40 mg/dL; (b)selecting two optical coherence tomography scan data lines, each scandata line having been obtained on or about the time period; (c)computing intensity differences between the two selected opticalcoherence tomography scan data lines by subtracting a first baselinescan data line (n) from a second, subsequent optical coherencetomography scan data line (n+1) at every point along the two selectedoptical coherence tomography scan data lines to generate an intensitydifference plot; and (d) using the intensity difference plot todetermine a multitude of offsets and a multitude of intervals toconstruct a glucose vector grid comprising a multitude of offset,interval pairs. In another embodiment, the glucose vector grid in step(d) of the method further comprises a percentage change valuecorresponding to each offset, interval pair. In another embodiment,wherein the method to obtain the percentage change value for eachoffset, interval pair comprises the steps: (i) calculating a first slopevalue for a line segment from the first baseline scan data line and asecond slope value for a line segment from the second, subsequentoptical coherence tomography scan data line for each potential offsetand interval pair; and (ii) calculating the difference between the firstslope value and the second slope value for each potential offset andinterval pair to obtain a percentage change value for each potentialoffset and interval pair.

In another embodiment, the method further comprises the steps: (e)determining a scattering coefficient proportional to a slope of eachoptical coherence tomography scan data line for each potential offset,interval pair; (f) creating a calibration curve correlating scatteringcoefficients and blood glucose values by performing a regressionanalysis, wherein each x-value comprises a scattering coefficientcorresponding to the scattering coefficient of an invasively obtainedblood glucose measurement and each y-value comprises the blood glucosevalue measured from each invasively obtained blood glucose measurement;(g) calculating a set of estimated blood glucose values from thescattering coefficients for each potential offset, interval pair; (h)refining the set of estimated blood glucose values; (i) averaging thesets of estimated blood glucose values for each point in time togenerate the calibration set; and (j) applying the calibrated sensorcomprising the calibration set and selected offset, interval pairs toall subsequent optical coherence tomography scans. In anotherembodiment, step (d) of the method further comprises the steps (i)identifying at least one data point in the intensity difference plotwhere intensity is 0, at least one data point having a maximum intensitysurrounding the at least one data point where intensity is 0, and atleast one data point having a minimum intensity surrounding the at leastone data point where intensity is 0; and (ii) identifying a potentialoffset range, wherein a first boundary of the potential offset range isthe at least one data point having a maximum intensity surrounding theat least one data point where intensity is 0 and a second boundary ofthe potential offset range is the at least one data point having aminimum intensity surrounding the at least one data point whereintensity is 0. In another embodiment, wherein the time period includesa blood glucose altering event. In another embodiment, the blood glucosealtering event is administering insulin. In another embodiment, theblood glucose altering event is eating a meal. In another embodiment,the blood glucose altering event is drinking a beverage containingsugar.

In another embodiment, refining step (h) of the method further comprisesthe step applying at least one statistical filter. In anotherembodiment, the statistical filter refines a set of average estimatedblood glucose values from each potential offset, interval pair byignoring sets of estimated blood glucose values that are outside onestandard deviation of the set of average estimated blood glucose valuesat any point in time. In another embodiment, the statistical filterrefines a set of median estimated blood glucose values by ignoring setsof estimated blood glucose values that are outside one standarddeviation of the set of median estimated blood glucose values at anypoint in time. In another embodiment, prior to generating thecalibration set of estimated blood glucose values, the at least onestatistical filter eliminates negative estimated blood glucose values.In another embodiment, prior to generating the calibration set ofestimated blood glucose values, the at least one statistical filtereliminates estimated blood glucose values of less than about 10 mg/dL.In another embodiment, prior to generating the calibration set ofestimated blood glucose values, the at least one statistical filtereliminates high estimated blood glucose values. In another embodiment,prior to generating the calibration set of estimated blood glucosevalues, the at least one statistical filter operates in accordance withequation (1). In another embodiment, prior to generating a calibrationset of estimated blood glucose values, the at least one statisticalfilter operates in accordance with equation (2).

In another embodiment, the method further comprising the steps (e)enhancing at least one discontinuity in each selected optical coherencetomography scan data line; and (f) using the at least one discontinuityto generate the potential offsets of the multitude of offset, intervalpairs. In another embodiment, step (e) of the method further comprisingthe step: generating a second derivative plot of the optical coherencetomography scan data line. In another embodiment, the method furthercomprises the step of identifying potential offsets by using the atleast one discontinuity. In another embodiment, the at least onediscontinuity indicates potential offsets that correlate closely tolocations of a tissue interface transition. In another embodiment, thetissue interface transition is a blood vessel. In another embodiment,the discontinuity corresponds to changes in blood glucose levels.

In another embodiment, calibration step (c) of the method furthercomprises the steps: (i) using a Pearson's plot to calibrate the opticalcoherence tomography-based sensor against at least two invasivelyobtained blood glucose measurements taken during the time period; and(ii) using Pearson's correlation to maximize the correlation betweendata received from the optical coherence tomography-based glucosemonitor and the invasively obtained glucose measurements. In anotherembodiment, the Pearson's plot in step (i) requires at least seven bloodglucose measurements invasively obtained over the time period.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure will be more readily understood from the detaileddescription of the embodiments presented below considered in conjunctionwith the figures herein, of which:

FIG. 1 is a graphical illustration of a typical scattering cross-sectionfrom a patch of human skin measured using an OCT-based blood glucosemonitor;

FIG. 2 illustrates how an offset and an interval are defined, accordingto an embodiment of the present disclosure;

FIGS. 3A and 3B illustrates a process flow of a method for calibratingan OCT-based blood glucose monitor, according to embodiments of thepresent disclosure;

FIG. 4 shows an example of an intensity difference plot, according to anembodiment of the present disclosure;

FIG. 5 shows an example of a glucose vector grid, according to anembodiment of the present disclosure;

FIGS. 6A and 6B illustrate process flows of a method for calibrating anOCT-based blood glucose monitor, according to embodiments of the presentdisclosure;

FIGS. 7A and 7B are graphical illustrations in which scatteringdiscontinuities are identified, according to an embodiment of thepresent disclosure;

FIG. 8 is contour plot illustrating Pearson's correlation coefficientscalculated for multiple pairs of offsets and intervals, according to anembodiment of the present disclosure;

FIG. 9 is a graphical illustration of estimated blood glucose levelswith a high correlation between an OCT signal and measured blood glucoselevels, according to an embodiment of the present disclosure, and

FIG. 10 is a graphical correlation between a high an OCT signal andmeasured blood glucose levels.

DETAILED DESCRIPTION

When using an OCT-based blood glucose monitor to measure blood glucoselevels or concentrations (also known as “serum glucose levels” or “sugarblood levels”) in a biological tissue, the light provided by theOCT-based blood glucose monitor scatters throughout the biologicaltissue. The scattering of light changes in response to variations inblood glucose levels. Specifically, a scattering coefficient, μ_(s),which describes the attenuation of light due to the scattering of lightby a biological tissue, rises and falls relative to variations in bloodglucose levels. In accordance with the present disclosure, the bloodglucose concentration or level within a biological tissue is monitoredby providing a wavelength of light for which the attenuation isdominated by scattering effects and not absorption effects (i.e., suchas absorption by water or hemoglobin), and continuously scanning thelight over a two dimensional area of the biological tissue while, at thesame time, interferometrically scanning the biological tissue in a depthdimension. By using a coordinate system defined so that the x-y axisforms the plane of the surface of the skin and the z axis is into theskin and parallel with the optical axis of the system, the term “depthdimension” refers to the dimension perpendicular to the surface of theskin and parallel with the optical axis of the system. The lightreflected from the scanned biological tissue is collected and analyzedto determine the concentration of glucose in the biological tissue.

The present disclosure relates to a method for calibrating an OCT-basedblood glucose monitor by maximizing the correlation between dataproduced by the OCT-based blood glucose monitor and measured bloodglucose concentrations or levels. In one aspect of the presentdisclosure, an OCT scan data line can be utilized to maximize thecorrelation between the data received from the OCT-based blood glucosemonitor and the measured blood glucose levels. As used herein, the term“scan data line” refers to the line formed from data obtained throughthe average of multiple OCT scans; the plot of this data is a plot ofinterferometric intensity versus depth. The scan data line, which is theaverage of multiple depth scans at different x-y locations over a givenarea, is an ensemble average of the scattering coefficient, as afunction of depth, of the tissue volume being scanned.

In another aspect of the present disclosure, the Pearson Product Momentcorrelation method (Pearson's correlation) is utilized to maximize thecorrelation between the data received from the OCT-based blood glucosemonitor and the measured blood glucose levels. Correlation results areused to calibrate the OCT-based blood glucose monitor, which then may beused to provide estimated blood glucose levels. Instead of determiningblood glucose levels by current invasive methods, the blood glucosevalue obtained according to the present disclosure is estimated.Technically speaking then, a calibrated OCT glucose monitor according tothe present disclosure provides a blood glucose level based on acalibrated prediction. The OCT-based blood glucose monitor thus may beused to provide estimated blood glucose levels to a user of the bloodglucose monitor monitoring blood glucose levels, of for example, adiabetic subject, or of a subject with hyperglycemia (meaning high bloodglucose levels, for example, ≧126 mg/dL), or of a subject withhypoglycemia (meaning low blood glucose levels, for example, ≦70 mg/dl).

According to an embodiment of the present disclosure, a method ofcorrelating the OCT-based blood glucose monitor data with measured bloodglucose levels includes a user taking multiple blood glucosemeasurements over a specified time period, preferably including a mealduring that period, using a standard invasive method. The OCT-basedblood glucose monitor uses a specific wavelength of light such that anabsorption coefficient of light, μ_(s), of the biological tissue of theuser is low relative to the scattering coefficient of light, μ_(s),within the biological tissue in order for variations in scattering ofthe light to be dominated by glucose-induced changes in scatteringcaused by the biological tissue. Multiple OCT scans are obtained at oraround the same time period as when the blood glucose measurements aretaken so that there is at least one OCT scan line per blood glucosemeasurement. The multiple OCT depth scans, which are averaged togetherto form the scan data line, should be accumulated within no more thanabout 5 min from the time the blood glucose value is determined. Datafrom each OCT scan is an averaged value of data obtained from aplurality of OCT scans performed automatically by the OCT-based bloodglucose monitor in order to reduce any coherent noise or speckleproduced by the OCT-based monitor itself. The data may be stored in theOCT-based blood glucose monitor or, alternatively, a programmablecomputer. OCT data provided by each averaged OCT scan may be plotted asinterferometric intensity against the depth of the biological tissue, oragainst a set of depths of the biological tissue.

Due to the inherent heterogeneity of biological tissue and the unevendistribution of blood vessels in the dermis layer of biological tissue(i.e., the layer of skin beneath the epidermis), which is the preferredlayer of skin for locating blood vessels, only specific segments orportions of an OCT scan-data line correlate to the actual blood glucoselevels. Additionally, by knowing the specific wavelength oflight-chosen, the dermis region of the biological tissue (e.g., ofskin), which is where most blood vessels lie, may be determined easilyfrom the data produced by the OCT-based blood glucose monitor.

There are two variables or parameters associated with fitting theobtained OCT data to the obtained blood glucose measurements in order toachieve the best correlation. These variables are an offset and aninterval. The term “offset” as used herein refers to the depth of theOCT scan-data line/data curve) at which to begin correlating the OCTdata to the blood glucose measurements, preferably in the dermis regionof the biological tissue (e.g., of skin). This depth is referenced tothe surface of the skin located at the skin/optical window interface.The term “interval” as used herein refers to a certain portion orsegment of the OCT scan-data line that is measured from the offset. Todetermine the slope of any line segment, a linear least squares fitcalculation generally is used to find the slope of the line.Alternatively, one can take the derivative of the line using any of anumber of algorithms, one example of which is the finite difference,which is defined as subtraction of one adjacent point from anotheradjacent point. For each OCT scan-data line there are numerous potentialcombinations or pairs of offsets and intervals. The present disclosurereduces the number of potential pairs of offsets and intervals to pairsthat are closely correlated to the measured blood glucose levels.

Blood glucose typically is represented either as a weight per unitvolume by milligrams per deciliter (mg/dl) or as a molecularconcentration in millimoles per liter (mM/L). A blood glucose level of 1mM/L is equal to a level of 18 mg/dL. According to one aspect-of thepresent disclosure, the algorithm of the present disclosure selects twoinvasively measured blood glucose levels or blood glucose points thatare spaced apart by a weight value of at least about 40 mg/dL, or about2 mM/L. As soon as the algorithm sees two blood glucose levels more thanabout 40 mg/dL apart, it will begin the calibration process, which isdepicted as box number 1 (S301) in FIG. 3 b. The algorithm then selectstwo OCT scans taken at or around the same time as the selected bloodglucose points. The selected OCT scans are used to reduce the dataproduced by the OCT-based blood glucose monitor to data that is closelycorrelated with the blood glucose measurements. Optionally, thealgorithm may select several (averaged) OCT scans temporally locatedaround the selected blood glucose points and average the data from theselected OCT scans in order to further reduce the speckle associatedwith the OCT-based blood glucose monitor.

The term “intensity difference plot (“IDP”)” refers to a plot in which abaseline OCT scan (scan n) is subtracted from a subsequent OCT scan(scan (n+1)) to provide information on what regions of the scan linehave changed from scan n to scan (n+1). According to the presentdisclosure, an intensity difference plot is generated by computing thedifference in the intensity data of the two selected OCT scans. Theintensity difference in the intensity data of the two selected OCT scans(the “intensity difference”) is plotted against the depth of the testedbiological tissue. With the present disclosure, it has now been observedthat certain portions of an OCT scan-data line change dramatically asblood glucose levels vary, while certain other portions of an OCTscan-data line remain static as blood glucose levels vary. The intensitydifference plot identifies the regions of the selected OCT scan-datalines that have the highest change in intensity. This change inintensity closely correlates (i.e., >95% confidence limit) to changes inblood glucose levels. Such dramatic changes in intensity also correlateclosely (i.e., within a >95% confidence limit) to locations of a tissuetransition interface, based on the depths of the tested biologicaltissue that corresponds to the changes in the intensity of the OCTsignal. While one example of such a tissue transition interface is ablood vessel in the skin, structures other than blood vessels in theskin also could be changing with blood glucose levels. Blood vessels inthe skin generally are fairly randomly distributed macroscopically andmicroscopically. However, there are capillaries (seen at the dermisepidermis junction), venules, and arterioles, which lie closer to thedermis-subcutaneous junction. The OCT correlations of the presentdisclosure occur at depths in the skin where these blood vesselsreasonably can be expected to be located. The algorithm generates anintensity difference plot to determine potential offsets that correlateclosely to the selected blood glucose points.

An intensity difference plot has a characteristic peak-to-valley patternthat crosses zero at one or more certain depths. The greatest change inan intensity difference plot occurs at depths surrounding thezero-crossing point(s) in the data line. The algorithm identifies thezero-crossing point(s) and identifies localized extrema (i.e., localizedminimum and maximum data points) on either side of the zero-crossingpoint(s). Because the range of data falling within the localized extremasurrounding the zero-crossing point(s) represents the greatest change inthe data provided by the OCT scans, potential offsets that correlateclosely to the selected blood glucose points lay within this range ofdata. Once the algorithm identifies the localized extrema associatedwith the zero-crossing point(s), it determines the potential offsets.Optionally, the algorithm may include offsets within a certain varianceof the localized extrema.

The percentage change in the slopes of the OCT signals for a givenchange in blood glucose levels depends on the sensor design. Generally,individual subjects fit within a small percentage range, which is withinan order of magnitude. For a given sensor design, it is necessary tofind the mean of that range and determine the standard deviation aroundthe mean. These values are determined empirically through a calibrationsubset. Typically, about 30 to about 40 subjects are obtained acrossdifferent age and racial demographics for a given sensor design. Fromthat group, the algorithm would derive a filter percentage based on themean and standard deviation about the mean. The filter percentage formsthe vector for the glucose vector grid part of the algorithm. The finalnumbers used in the vector grid filter will depend on the sensor design.In one particular design, the relevant physiologic range of thepercentage change is about 2% per 18 mg/dL to about 20% per 18 mg/dL. Inother sensor designs, the mean could be higher.

In some embodiments of the present disclosure, in order to identifypotential offset and interval combinations or pairs that closelycorrespond to the selected blood glucose points, the algorithm utilizespotential offsets identified from the intensity difference plot togenerate a glucose vector grid he relevant physiologic range of thepercentage change depends on physiologic factors as well as the size anddepth of the tested region of biological tissue. The glucose vector gridis a table whose x-coordinates are the offset values and whosey-coordinates are the interval values. The calculated positivepercentage changes are entered for each offset and interval pair to formthe grid. Each (x, y) coordinate of the grid contains the percentagechange in the signal based per 18 mg/dL of glucose. In some embodimentsof the present disclosure, to generate the glucose vector grid, thealgorithm determines the slope values for multiple combinations ofintervals and potential offsets for the two selected OCT scans, using acommon slope calculation, such as, for example, a linear least-squaresfit calculation. The algorithm then determines the difference in theslope values for each offset and interval combination/pair between thetwo selected OCT scans, and represents the slope difference as apercentage change between the two selected OCT scans.

For each potential offset and interval pair, the scattering coefficient,can be determined. More specifically, in some embodiments of the presentdisclosure, a potential offset and interval pair can be chosen and theslope of the OCT scan-data line segment corresponding to the chosenoffset and interval pair is computed using a common slope calculation,such as, for example, a linear least-squares fit calculation. Thescattering coefficient, μ_(s), is proportional to the slope of the OCTscan-data line segment that corresponds to the chosen offset andinterval pair, and is calculated for each of the OCT scans, which areaveraged, so that the chosen offset and interval pair has a number ofassociated scattering coefficients, μ_(s), equal to the number of themultitude of OCT scans. This process then is repeated for each potentialoffset and interval.

The scattering coefficient, μ_(s), corresponding to an offset, intervalpair, is proportional to an associated slope value. Estimated bloodglucose levels, which are used to calibrate the OCT-based sensor, asdiscussed below, are related to the scattering coefficients, μ_(s),either proportionally or inversely proportionally. Thus, changes in theslope of an OCT signal (and thus, changes in the scattering coefficient,μ_(s)) correlate to changes in blood glucose levels. When blood glucoselevels are increasing, the scattering coefficients, μ_(s), decrease(i.e., the slopes of the OCT signal decrease) because the scatter oflight by the biological tissue decreases. This translates into anegative percentage-change value for an increase in blood glucoselevels. Accordingly, when blood glucose levels are decreasing, thescatter of the light by the biological tissue increases, and thus, thescattering coefficients, μ_(s), (i.e., the slopes of the OCT signal)increase. This translates into a positive percentage-change value for adecrease in blood glucose levels.

Once the algorithm has generated sets of estimated blood glucose levels,it may refine the sets of estimated blood glucose levels by applying oneor more statistical filters. The order in which the statistical filtersare applied may be varied. The algorithm is hard coded to make thedecision of whether to accept a given offset, interval pair in the gridbased on a range determined from data obtained from a large pool ofsubjects for a given sensor configuration. Thus, for example, thealgorithm may be hard coded to choose a range of percentage-changevalues of about 4% to about 8% of the slope of the segment of the OCTscan line. The algorithm will generate a slope of the segment of the OCTscan line and a set of estimated blood glucose levels for each offset,interval pair that has a percentage-change value between about 4% andabout 8% using all of the OCT scans taken during the specified timeperiod.

One filtering option eliminates sets of estimated blood glucose levelsthat contain negative or unusually small (less than about 10 mg/dL)estimated blood glucose levels. Thus, if the calculated percentagechange of a given offset, interval pair is below the established lowvalue, that pair is discarded. Another filtering option eliminates setsof estimated blood glucose levels that contain unusually high estimatedblood glucose levels (i.e., more than about 500 mg/dL). Thus, if thecalculated percentage change of a given offset, interval pair isunusually high, that pair is discarded. This leaves behind offset,interval pairs which are reasonable.

After applying at least one filter, the algorithm uses the remainingset(s) of estimated blood glucose levels to calibrate the OCT-basedblood glucose monitor. The algorithm then averages the estimated bloodglucose values to generate one averaged estimated blood glucose valuethat is associated with the new averaged OCT scan and calibrates theOCT-based blood glucose monitor with this averaged estimated bloodglucose value.

For positive percentage-change values, an estimated blood glucose levelis equal to the negative value of the slope value associated with thecorresponding offset and interval pair. For negative percentage-changevalues, an estimated blood glucose level is equal to the negativeinverse of the slope value associated with the corresponding offset andinterval pair. Because each offset and interval pair has one associatedslope value for each OCT scan, each offset, interval pair produces a setof scattering coefficients, the number of which will equal the number of(averaged) OCT scans taken during the specified time period. Optionally,depending on the tested area of the biological tissue, the algorithm mayvary the range of percentage-change values in order to produce differentsets of potential offset and interval pairs.

The algorithm creates a calibration curve correlating scatteringcoefficients and blood glucose values by performing a regressionanalysis, wherein each x-value comprises a scattering coefficientcorresponding to the scattering coefficient of an invasively obtainedblood glucose measurement and each y-value comprises the blood glucosevalue measured from each invasively obtained blood glucose measurement.Once the OCT data has been transformed into calibrated blood glucoselevels, the “biological relevance” of the data (including, but notlimited to, whether the estimated blood glucose level changed too fastto be real, whether the estimated blood glucose level is negative, orwhether the estimated blood glucose level goes too high) can bedetermined by a simple linear regression of the paired blood glucose/OCTpoints. For example, one embodiment of the present disclosure comprisesa home monitor in which the estimated blood glucose level would neverreach > about 500 mg/dL. Typical blood glucose test strips do not readsuch a high blood glucose level.

Another aspect of the present disclosure includes refining the estimatedblood glucose levels by calculating an average estimated blood glucoselevel for each point in time associated with the testing time period.The algorithm selects a first point in time and averages the estimatedblood glucose levels corresponding to the first point in time at which afirst (averaged) OCT scan was taken for each offset and interval pair.The algorithm then repeats the process for each point in time andgenerates a set of average estimated blood glucose levels equal to thenumber of averaged OCT scans taken. It is possible to put a repeatedglucose requirement at certain intervals in the algorithm. For example,the algorithm can require a new glucose value every once an hour, asoften as every estimated OCT glucose point, or every 12 hours.Generally, further calibration of the OCT-based blood glucose monitor ofthe present disclosure would not be required. However, in alternateembodiments, the algorithm is reapplied at particular intervals torecalibrate the OCT-based blood glucose monitor.

The algorithm calculates a standard deviation for each average estimatedblood glucose level, uses the average estimated blood glucose level andthe corresponding standard deviation for the first point in time, andcompares each estimated blood glucose level from each set of estimatedblood glucose levels at the first point in time. If an estimated bloodglucose level at the first point in time falls outside one standarddeviation of the average estimated blood glucose level, the entire setof estimated blood glucose levels and, accordingly, the correspondingoffset and interval, are ignored. The algorithm repeats this process foreach point in time and each corresponding average estimated bloodglucose level and the associated standard deviation. The remainingset(s) of estimated blood glucose levels form a calibration data set,i.e., the estimated blood glucose levels that are within one standarddeviation of the average estimated blood glucose level form acalibration data set for calibrating the OCT-based blood glucosemonitor. If more than one set remains, a final calibration data set ofestimated blood glucose levels is computed by taking the average of theremaining sets of estimated blood glucose levels for each point in time.

Optionally, the algorithm may calculate a median estimated blood glucoselevel for each point in time and may calculate corresponding standarddeviation values. The algorithm then uses the median estimated bloodglucose level and the corresponding standard deviation for the firstpoint in time and compares each estimated blood glucose level from eachset of estimated blood glucose levels at the first point in time.Similar to the process described above, if an estimated blood glucoselevel at the first point in time falls outside one standard deviation ofthe median estimated blood glucose level, the entire set of estimatedblood glucose levels and, accordingly, the corresponding offset andinterval, are ignored. The algorithm repeats this process for each pointin time and each corresponding median estimated blood glucose level andthe associated standard deviation. The remaining set(s) of estimatedblood glucose levels form a calibration data set. If more than one setremains, a final calibration data set of estimated blood glucose levelsis computed by taking the average of the remaining sets of estimatedblood glucose levels for each point in time.

Optionally, the algorithm may calculate both an average estimated bloodglucose level and a median estimated blood glucose level and standarddeviation for each point in time and use both the average and the medianestimated blood glucose levels to refine the sets of estimated bloodglucose levels, as described above for each.

To apply the calibration set of estimated blood glucose levels to anOCT-based blood glucose monitor, the algorithm performs a new OCT scanat a new time. The algorithm then computes a new estimated blood glucoselevel for the new OCT scan using the calibration set of estimated bloodglucose levels and the corresponding offset and interval pair. If morethan one set of estimated blood glucose levels was used to generate thecalibration set, the algorithm may use each set of estimated bloodglucose levels and the associated offset and interval pairs to computecorresponding new estimated blood glucose levels, i.e., a new estimatedblood glucose level for each offset and interval pair. The algorithmthen averages the new estimated blood glucose levels to generate one newestimated blood glucose level for the new point in time.

According to another embodiment of the present disclosure, potentialoffsets that correlate closely to blood glucose levels may be determinedby utilizing the change in the slope of the OCT scan-data line as afunction of the depth of the biological tissue. Specific structures,such as blood vessels, in the biological tissue may scatter the light ofthe OCT scan differently than the surrounding tissue and medium and mayproduce discontinuities in the OCT scan data, even though the bloodglucose level is not changing. The term “medium” is used herein todescribe the relatively homogeneous structures in the skin, including,but not limited to, skin cells, the collagen/elastin fiber matrix,interstitial fluid, and the like. An object, including but not limitedto a blood vessel, has a very different scattering profile than thismedium. This different scattering profile provides a characteristicsignal that can be used to identify the tissue depth at which thescattering will correlate to glucose.

The term “discontinuity” as used herein refers to an identifiable,abrupt change in the OCT scan line indicating a tissue interfacetransition. Most simply, a discontinuity appears as a “bump” on theslope of an otherwise straight line. For example, in FIG. 1, at about2.9 on the depth scale, a bump, which is a discontinuity in the line, isassociated with a blood vessel. The presence of, a tissue interfacetransition, for example, a blood vessel, therefore causes an abruptchange in the intensity. Such discontinuities allow the algorithm toidentify potential offsets that correlate closely (>95% confidencelevel) to blood vessels.

According to one aspect of the present disclosure, the algorithm mayidentify the discontinuities in the OCT scan-data lines by computing thesecond derivative of the OCT scan data and then computing the squaredvalue of the second derivative. The discontinuities, which may not bevisible initially in an intensity plot, are enhanced by calculating thesecond derivative of the OCT scan data. Squaring the data results of thesecond derivative calculation ensures that the resulting data resultsare positive. Because the discontinuities are enhanced, thediscontinuities are visible as “spikes” or bumps along the new OCTscan-data line. Offsets that correspond to the discontinuities representpoints along the OCT scan-data line closely correlated to blood vessels.The algorithm identifies offsets that correspond to the discontinuitiesand generates a glucose vector grid, as discussed above. Optionally, thealgorithm may utilize both an intensity difference plot and a secondderivative plot to identify potential offsets.

Once the algorithm has identified acceptable offset, interval pairs andgenerated the appropriate calibration factors, every time the calibratedOCT-based blood glucose monitor is employed to generate a new OCT scan,the algorithm will apply the acceptable offset, interval pairs andcalibration factors to subsequent scans.

In some embodiments of the present disclosure, the Pearson's correlationmethod (i.e., the “Pearson Product Moment Correlation” method, oftenreferred to as “Pearson's correlation coefficient”) is used to determinethe degree of a linear relationship between the scattering coefficients,μ_(s), and the measured blood glucose levels. Changes in the slopes ofthe OCT scan-data line, i.e., changes in the scattering coefficients,μ_(s), are either proportionally related or inversely proportionallyrelated to changes in the level of blood glucose. By using the Pearson'scorrelation coefficient to determine which scattering coefficients,μ_(s), closely correlate to the measured blood glucose levels, thealgorithm may determine an optimal offset and interval pair to choosefor calibrating the OCT-based monitor.

The Pearson's correlation coefficient ranges between minus 1.0 (−1.0) topositive 1 (+1.0). A coefficient value of +1.0 indicates a perfectcorrelation between two variables, that is, a perfect positive linearrelationship exists between the two variables. The linear relationshipis usually represented by a scatter plot (meaning a visual displayshowing the numerical data of one variable plotted against the numericaldata of a second variable where each data point has a coordinate on ahorizontal and vertical axis). A perfect correlation coefficient valueof +1.0 also indicates that as values of one variable increase, e.g.,along an x-axis, values of the other variable increase correspondingly,e.g., along a y-axis, and all values lie along a single line. APearson's correlation coefficient value of −1.0 indicates a perfectinverse linear relationship between two variables, that is, as valuesalong the x-axis increase, values along the y-axis decreasecorrespondingly. A Pearson's correlation coefficient value of 0.0indicates that no correlation exists between the two variables, i.e.,the values are so scattered that it is impossible to determine a linearrelationship between values for the two variables.

In some embodiments of the present disclosure, a Pearson's correlationcoefficient is generated to correlate the scattering coefficientsassociated with each potential offset, interval pair to the measuredblood glucose levels. The process is repeated for each potential offset,interval pair in order to generate a set of Pearson's correlationcoefficients. The Pearson's correlation coefficients then may berepresented graphically as a contour plot against the potential offsetand interval pairs. Offset and interval pairs that produce Pearson'scorrelation coefficients at or near a value of +1.0 (i.e., high positivePearson's correlation coefficient values) indicate that the scatteringcoefficients, Us, associated with the slopes, which are derived from alinear fit corresponding to offset, interval pairs, correlate closely tothe measured blood glucose levels. In other words, for a given set ofblood glucose levels and an associated set of scattering coefficients,μ_(s), high positive Pearson's correlation coefficients indicate aconstant linear relationship between the two sets of data, and,accordingly, a close correlation. The algorithm may select a preferredrange of Pearson's coefficient values in order to select correspondingoffset, interval pairs for calibrating the OCT-based blood glucosemonitor.

Additionally, offset, interval pairs that have Pearson's coefficientvalues at or near a value of −1.0 (i.e., a high negative Pearson'scorrelation coefficient) also represent areas where the scatteringcoefficients, μ_(s), associated with the offset, interval pairs closelycorrelate to the measured blood glucose levels. A high negativePearson's correlation coefficient indicates that the scatteringcoefficients, μ_(s), associated with the slopes, which are derived froma linear fit corresponding to offset, interval pairs, are closelycorrelated to the measured blood glucose values, but that the slopevalues, and, therefore, the scattering coefficients, μ_(s), arenegative. The offset, interval pairs that produce high negativePearson's correlation coefficients also may be used to calibrate theOCT-based blood glucose monitor. The range of preferred Pearson'scorrelation coefficients is adjustable according to the needs of thealgorithm. All other offset, interval pairs that do not produce aPearson's correlation coefficient within such preferred range(s) areignored.

To calibrate the OCT-based blood glucose monitor, the algorithm selectsan offset, interval pair with a desired Pearson's correlationcoefficient, and calculates the scattering coefficient, μ_(s), for eachportion of each averaged OCT scan-data line that corresponds to theselected offset, interval pair. The scattering coefficients, μ_(s),corresponding to the selected offset, interval pair are plotted with themeasured blood glucose levels against the specified time period todisplay how closely correlated the OCT-based blood glucose monitor datais to the measured blood glucose value or level. If the algorithm issatisfied with the correlation, it may calibrate the OCT-based bloodglucose monitor according to the scattering coefficients, associatedwith the selected offset, interval pair in order to compute estimatedblood glucose levels. The terms “estimated” and “predicted” are usedinterchangeably herein. An estimated blood glucose level is computed bytaking the negative of the scattering coefficient value for the selectedoffset, interval pair. For a selected offset, interval pair that has ananti-correlated scattering coefficient value, a corresponding estimatedblood glucose level is computed by taking the negative inverse of thescattering coefficient value.

If the algorithm is not satisfied with the correlation produced by theselected offset, interval pair, it may select another offset, intervalpair according to the corresponding Pearson's correlation coefficientuntil a desired result is reached. Once the algorithm has identifiedacceptable offset, interval pairs and generated the appropriatecalibration factors, every time the calibrated OCT-based blood glucosemonitor is employed to generate a new OCT scan, the algorithm will applythe acceptable offset, interval pairs and calibration factors tosubsequent scans.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges which may independently be included inthe smaller ranges is also encompassed within the disclosure, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs.

Any methods and materials similar or equivalent to those describedherein also can be used in the practice or testing of the presentdisclosure.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited.

Examples

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present disclosure, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

FIG. 1 shows an intensity profile of light scattered from a biologicaltissue (human skin) as measured via an OCT-based blood glucose monitoraccording to an embodiment of the present disclosure. If an appropriatewavelength of light is chosen (e.g., about 1300 nanometers) such thatthe absorption coefficient of the light, μ_(s) is small relative to thescattering coefficient of the light (for example, if the scatteringcoefficient is five times the absorption coefficient), μ_(s), by thebiological tissue, then a change in the slope of the OCT scan-data linelikely will be dominated by glucose-induced changes in the tissuescattering. Based on the wavelength of light chosen, the OCT-based bloodglucose monitor signal spikes at certain regions of the surface of thebiological tissue and then falls dramatically within the epidermisregion of the skin. The OCT scan-data line then rises and slowlydecreases within the dermis region as the depth of light in thebiological tissue (e.g., skin) increases. Because most blood vessels arelocated in the dermis region, it is this portion of the OCT scan-dataline that provides data for calibrating the OCT-based blood glucosemonitor. As shown in FIG. 1, the slope of the OCT scan-data line mayincrease or decrease relative to the blood glucose level. That is tosay, the slope of the OCT scan-data line decreases as the blood glucoselevel increases, and, accordingly, the slope of the OCT scan-data lineincreases as the blood glucose level decreases.

FIG. 2 illustrates the two parameters used to maximize the correlationbetween the OCT-based blood glucose monitor data and the measured bloodglucose levels. The first parameter, the offset, is the depth at whichto begin determination of the correlation of the OCT scan-data line tothe measured blood glucose levels. The offset is measured from the spikein the OCT scan-data line, which represents the surface of thebiological tissue (e.g., skin) to a particular depth within the dermislayer of the biological tissue (e.g., skin). The second parameter, theinterval, is the portion of the OCT scan-data line used to correlate theOCT data to the measured blood glucose levels. The interval is measuredfrom the offset depth and can be any length according to the algorithm'sneeds; for example, the length can range from a value about equal to thedifference between adjacent points of the OCT scan-data line (whichapproximates the derivative of the line) to about 1 mm (used with alinear least squares fit calculation to find the slope). Given the depthof the entire OCT signal, there are multiple combinations of offsets andintervals that may be used for correlating the OCT data. For example,three offset, interval pairs may be: an offset of about 300 microns andan interval of about 50 microns; an offset of about 300 microns and aninterval of about 150 microns; and an offset of about 700 microns and aninterval of about 100 microns.

In some embodiments of the present disclosure, the method for reducingthe amount of data necessary to calibrate an OCT-based blood glucosemonitor is as summarized in the flow chart shown in FIG. 3. FIG. 3,together with the graphs of FIG. 4 and FIG. 5, presents a process flowof a method for maximizing the correlation between the OCT-based bloodglucose monitor data and measured blood glucose levels, and using thatcorrelation to calibrate the OCT-based blood glucose monitor, accordingto an embodiment of the present method. The steps of the method need notbe taken in the sequence illustrated. As shown in FIG. 3 b, Step S302may be implemented at the same time as Step S303, i.e., they need not berun sequentially, as shown in FIG. 3 a. Over a period of time, a usertakes a number of invasively-obtained blood glucose measurements (seee.g., S301 of FIG. 3) to measure the level of blood glucose over a givenperiod of time, for example, 190 minutes. Since a glucose change must berecorded in the blood glucose levels by both conventional blood glucosechemistry and the OCT value for correlation purposes, given that themaximum a human subject's blood glucose can change is about 5 mg/dL permin (average is about 2 mg/dL) it would take about 4 minutes to about 10minutes to get a reasonable blood glucose spread in values.

A minimum of two invasively obtained blood glucose measurements (orpoints) is required for the IDP/glucose vector grid approach asdescribed above, although more measurements can be used. In the Pearsonapproach, a minimum of seven invasively obtained blood glucosemeasurements (or points) is needed for statistical confidence. In someembodiments of the present disclosure, the time period includes a bloodglucose altering event, such as, but not limited to, subject-initiatedevents, e.g., eating a meal, administering insulin, drinking a beveragecontaining sugar (e.g., juice) and the like. It is understood that oneor more blood glucose altering event also can occur on its own.

Over the same period of time (e.g., 190 minutes), the algorithm takesmultiple OCT scans using the OCT-based blood glucose monitor such as,for example, about 100 OCT to about 1500 scans for a 190-minute period(S302 of FIG. 3). Although the number of OCT scans taken is at thediscretion of the algorithm, the number of OCT scans taken cannot beless than the number of blood glucose measurements taken during the timeperiod. Each OCT scan is an average of a number of OCT scans, forexample, about 1500 OCT scans, in order to reduce the effects of anynoise or speckle produced by the OCT-based blood glucose monitor.

Once the blood glucose measurements and OCT scan data are acquired (S301of FIG. 3), the algorithm selects two invasively obtained measured bloodglucose levels, or points, that are at least 40 mg/dL apart in value.The algorithm also selects two OCT scans that correspond to points intime of the selected blood glucose points. The algorithm creates anintensity difference plot (IDP) by calculating the difference betweenthe data of the two selected OCT scans (S302 of FIG. 3)) FIG. 4 shows anexample of an intensity difference plot according to the presentdisclosure. In FIG. 4, the algorithm has selected invasively obtainedmeasured blood glucose point 2 (BG #2) and invasively obtained measuredblood glucose point 5 (BG #5) to calibrate the OCT-based blood glucosemonitor. The algorithm then selects two OCT scans that correspond topoints in time of BG #2 and BG #5 and computes the difference in thedata between the two selected OCT scans. The algorithm identifies one ormore zero-crossing points in the intensity difference plot as well aslocalized extrema surrounding the zero-crossing points, respectively.The intensity difference plot in FIG. 4 has one zero-crossing point,which is located at a depth of about 225 microns. A local maximum datapoint is located at about 200 microns and a local minimum point islocated at about 350 microns. The depths within the region of thelocalized extrema represent potential offsets that are closelycorrelated to the selected blood glucose points and are represented inFIG. 4 by a shaded box. Optionally, the algorithm may expand the box toinclude potential offsets within a variance amount of the localizedextrema. For example, in FIG. 4, the range of potential offsets includesoffsets from about 175 microns to about 400 microns.

Next, the algorithm takes the range of potential offsets from theintensity difference plot and generates a glucose vector grid, whichproduces potential offset and interval pairs that closely correlate tothe selected blood glucose points. (See, S303 of FIG. 3). Every offset,interval pair has an associated slope value for each OCT scan. The slopevalue is determined using a common calculation, such as, for example, alinear least squares fit calculation. Utilizing the two selected OCTscans, the algorithm calculates two slope values for each potentialoffset and interval pair and then calculates the difference in the twoslope values as a percentage change from the OCT scan that occursearlier in the testing time period to the OCT scan that occurs later inthe testing time period. The percentage-change values (or percent signalchange values) are tabulated against the corresponding offset, intervalpairs.

As shown in step S304 of FIG. 3, the algorithm identifies thepercentage-change values that fall within a certain physiological rangepredetermined by the algorithm for a particular sensor design. The rangeis set based on the sensor's measured response as measured in apopulation of a representative set. For example, in one particularsensor design, changes in blood glucose levels range from about 2% toabout 20% for every 18 mg/dL. For this sensor design, the algorithm mayidentify percent signal change values that fall within the range ofabout 2% and about 20% and ignore offset and interval pairs that do notcorrespond to this range. Alternatively, the algorithm may minimize therange to isolate a smaller number of potential offset, interval values.

Additionally, when the algorithm takes the range of potential offsetsfrom the intensity difference plot and generates a glucose vector grid(S303 of FIG. 3), it may generate a glucose vector grid for offset,interval pairs that have negative percentage-change values. In such anembodiment of the present disclosure, the algorithm may apply analternate physiological range of percentage-change values, such as, forexample, −20% to −2%, to reduce the number of potential offset, intervalpairs that closely correlate to the selected blood glucose points (seee.g., S304 of FIG. 3). An example of a glucose vector grid for offset,interval pairs with negative percentage-change values is presented inFIG. 5.

The slope values of the identified offset, interval pairs are convertedinto estimated blood glucose values (S305 of FIG. 3). For example, ifthe first invasively obtained measured blood glucose point, BG #2, wasmeasured at about 100 mg/dL and the algorithm selected a range of offsetand interval pairs with percentage-change values between about minus10.00 (−10.00) to about minus 10.20 (−10.20), then using the glucosevector grid in FIG. 5, this range of percentage-change values wouldcorrespond to four offset and interval pairs, (1) about 175 microns andabout 100 microns, (2) about 175 microns and about 125 microns, (3)about 225 microns and about 75 microns, and (4) about 250 microns and 50microns, respectively. This translates into generating sets of estimatedblood glucose values for each of the four offset, interval pairs. Inthis example, the scattering coefficient, μ_(s), for each of the fouroffset, interval pairs is calculated and associated with the firstinvasively obtained measured blood glucose point BG #2 of about 100mg/dL taken at the first point in time as a baseline. Scatteringcoefficients, μ_(s), then are computed for all the OCT scans taken afterthe first point in time for each offset, interval pair. Since thepercentage-change value is negative for each offset, interval pair,estimated blood glucose values are computed by taking the negativeinverse of each scattering coefficient, μ_(s). This computation producesfour sets of estimated blood glucose levels, which are used to calibratethe OCT-based blood glucose monitor. The algorithm may further refinethe four sets of estimated blood glucose values by ignoring sets thatcontain negative estimated blood glucose levels and/or sets withestimated blood glucose levels that are below a predetermined cutofflevel or above a predetermined cutoff level. The algorithm then maygenerate a calibration set of estimated blood glucose levels using theremaining set of estimated blood glucose levels. If more than one setremains, the algorithm may average the estimated blood glucose levels ateach point in time to produce a calibration set of estimated bloodglucose levels.

In some embodiments of the present disclosure, the algorithm can refinefurther the set of estimated blood glucose levels prior to generating acalibration set by, for example, and without limitation, applyingstatistical filters (see, e.g., S305 of FIG. 3). The order in which thestatistical filters are applied may be varied. In one embodiment, thealgorithm selects the estimated blood glucose levels from the potentialoffset, interval pairs that correspond to the first point in time andcalculates an average estimated blood glucose level. The algorithm alsomay calculate a median estimated blood glucose level corresponding tothe first point in time. For example, if the algorithm has reduced thepotential offset, interval pairs to four (4) pairs, as previouslydescribed, then for a first point in time, the algorithm averages thefour estimated blood glucose levels. The algorithm then repeats thisprocess for each point in time to generate a set of average estimatedblood glucose levels and calculates a standard deviation for the set ofaverage estimated blood glucose levels. Accordingly, the algorithm maygenerate a set of median estimated blood glucose levels and a standarddeviation. The algorithm then refines the set of estimated blood glucoselevels by ignoring sets of estimated blood glucose levels that falloutside one standard deviation of the average estimated blood glucoselevel at any point in time and/or one standard deviation of the medianestimated blood glucose level at any point in time.

Alternately, in another embodiment, to further refine the set ofestimated blood glucose levels prior to generating a calibration set(see, e.g., S305 of FIG. 3), the algorithm may apply the computedaverage and median estimated blood glucose levels to refine the set ofestimated blood glucose levels using either or both of the followingequations:

BG _(Avg.) −A*BG _(Avg. S.D.) ≦BG≦BG _(Avg.) +A*BG _(Avg S.D.)   (1)

BG _(Median) −A*BG _(Median S.D.) ≦BG≦BG _(Median) +A*BG _(Median S.D.)  (2)

Where “BG_(Avg.)” is the computed average estimated blood glucose levelat a point in time, “BG_(Avg. S.D.)” is the computed standard deviationof the set of averaged estimated blood glucose levels, “BG” is aparticular estimated blood glucose level at any point in time, A is afilter variable with a range of about 0.1 to about 1, “BG_(Median)” isthe computed median estimated blood glucose level at a point in time,and “BG_(Median S.D.)” is the computed standard deviation of the set ofmedian estimated blood glucose levels. The filter variable, A, allowsthe algorithm to take less than the standard deviation, if desired. Theabove equations allow the algorithm to ignore sets of estimated bloodglucose levels that are outside a range corresponding to less than onestandard deviation.

The algorithm is left with one or more sets of estimated blood glucoselevels and corresponding offset and interval pairs to be used tocalibrate the OCT-based sensor (see e.g., S306 of FIG. 3). The algorithmthen averages the sets of estimated blood glucose levels for each pointin time to generate a calibration set of estimated blood glucose levels,and applies the calibration set to calibrate the OCT-based blood glucosemonitor.

FIGS. 6A and 6B are flow charts summarizing methods of the presentdisclosure for reducing the data necessary to calibrate an OCT-basedblood glucose monitor, where the methods have been modified from themethod of the present disclosure summarized in the flow chart of FIG. 3.In both FIGS. 6A and 6B, the algorithm takes a number of blood glucosemeasurements over a period of time. In some such embodiment, the timeperiod includes a meal. Over the same period of time, the algorithmtakes multiple OCT scans using the OCT-based blood glucose monitor. Oncethe blood glucose measurements and OCT data is acquired (S301), thealgorithm selects two measured blood glucose levels, or points, that areat least about 40 mg/dL apart in value. The algorithm also selects twoOCT scans that correspond to points in time of the selected bloodglucose points.

In FIG. 6A, S601, the algorithm generates a second derivative plot toenhance discontinuities in each selected OCT scan-data line. Asdiscussed above, and without being held to any particular theory, thediscontinuities likely correlate to a tissue interface transition, suchas, but not limited to blood vessels, and an area in the biologicaltissue comprising such tissue interface transitions is the preferredarea of the biological tissue for measuring the level of blood glucose.By emphasizing the discontinuities, the locations in depth of the tissueinterface transitions may be identified. Thus, the algorithm generatesthe second derivative plot to identify potential offsets that correlateclosely to blood vessels. The method according to FIG. 6A follows themethod of FIG. 3 after S601 (i.e., S303-S306 in FIG. 3 are used in themethod of FIG. 6A).

The method summarized in the flow chart in FIG. 6B combines the methodssummarized in the flow charts of FIG. 3 and FIG. 6A. That is to say, thealgorithm creates both an intensity difference plot (S302 of FIG. 3) anda second derivative plot (S601 of FIG. 6A). The algorithm thenidentifies potential offsets by using the region created around thezero-crossing point in the intensity difference plot and thediscontinuities identified in the second derivative plot (see, e.g.,S602 of FIG. 6B). The method according to FIG. 6B otherwise follows themethod of FIG. 3 (see, e.g., S301, S303, and S305-S306).

FIGS. 7A and 7B graphically illustrate how a second derivative plotenhances discontinuities in the OCT scan-data line, referred to as thescattering profile. In FIG. 7A, an OCT scan-data line is plotted againstthe depth of the scanned biological tissue. Discontinuities in the OCTscan-data line are identified by circles in the graph; however, thediscontinuities may be difficult to visualize. In FIG. 7B, a square of asecond derivative of the OCT scan-data line is plotted against the depthof the scanned biological tissue. The discontinuities in the OCTscan-data line are enhanced by the second derivative computation whilecalculating the square value of the second derivative removes anynegatives that may exist. The discontinuities correspond to changes inblood glucose levels and indicate potential offsets that closelycorrelate to tissue interface transitions, such as blood vessels.

FIG. 8 is an example of a calibration set of estimated blood glucoselevels generated by using the method described in FIG. 3. Although themethod utilizes two measured blood glucose points, FIG. 8 includes anadditional eight measured blood glucose points to emphasize the closecorrelation between the estimated blood glucose levels and the measuredblood glucose points.

According to another aspect of the present disclosure, a programmablecomputer for use in calibrating an OCT-based blood glucose monitor isprovided. The programmable computer includes at least one memory havingat least one region for storing computer-executable program code, and aprocessor for executing the program code stored in the memory. Theprogram code includes modules for performing the slope calculations anddetermining a maximum correlation between the OCT scan data and themeasured blood glucose levels. Slope can be calculated in many ways,including, but not limited to, linear regression. The averaged OCT scanlines are generated by adding the individual scans together and thendividing by the number of scans. Optionally, the programmable computerplots the scattering coefficients of the light, μ_(s), against themeasured blood glucose levels. In some embodiments, the programmablecomputer of the present disclosure functions to calibrate the OCT-basedblood glucose monitor. As used herein, the term “memory” refers to anelectronic computer memory. The term “computer-executable program code”as used herein refers to code, such as assembly code, or another higherlevel language compiled into machine languages, such as C. The term“processor” as used herein refers to a computer microprocessor, such asa Pentium chip. The term “modules” refers to modular softwarecomponents. The term “calculations” refers to linear least square fit,calibration, an IDP calculation and the like. The term “functions”refers to individual software components that do one form ofcalculation, such as addition, or something more complex, such as alinear regression.

In some such embodiments, an algorithm utilizes a computer forgenerating a glucose vector grid of the present disclosure. For example,when the algorithm takes the range of potential offsets from theintensity difference plot and generates a glucose vector grid (S303 ofFIG. 3B), the algorithm may download the OCT scan data into a computerand may enter the measured blood glucose levels. Upon doing so, thealgorithm may program the computer to generate intensity plots of eachaveraged OCT scan over time to visualize the results (see, e.g., theplots shown in FIGS. 1 and 2). The algorithm then may manually selectpotential pairs of offsets and intervals for continuing the correlationand calibration process, or the algorithm may program the computer toautomatically select potential pairs of offsets and intervals in orderto automate the process. At S304 of FIG. 3B, the scattering coefficient,μ_(s), is computed for each averaged OCT scan at a particular offset,interval pair. For example, given the numbers in the above example, eachoffset, interval pair is associated with 100 averaged OCT scans, and,thus, has 100 corresponding scattering coefficients, μ_(s). Thescattering coefficients, μ_(s), then may be stored in computer-readablememory for later use.

When slope values of the identified offset, interval pairs are convertedinto estimated blood glucose values (S305 of FIG. 3B), the algorithmselects an averaged OCT scan temporally located around a blood glucosemeasurement, and instructs the computer to compute the Pearson'scorrelation coefficient for each potential offset and interval pairtaken from the OCT scan. A contour plot is generated to visualize thePearson's correlation coefficients in relation to each offset, intervalpair, for example, as shown in FIG. 4. In FIG. 4, the x-axis representsthe potential offsets, starting at about 100 microns, and the y-axisrepresents the potential intervals, starting at about 50 microns andincreasing to about 500 microns. From the plot generated (S305 of FIG.3B), the regions of highest correlation can be seen. From the plot ofFIG. 4, the algorithm may choose one or more offset and interval pairswith a desired Pearson's correlation coefficient to calibrate theOCT-based sensor (see e.g., S306 of FIG. 3B).

The algorithm then may generate a contour plot for the measured bloodglucose levels and the averaged OCT scans temporally located near themeasured blood glucose level. For example, given eight measured bloodglucose levels, the algorithm may select eight OCT scans correspondingin time to the eight measured blood glucose levels. The algorithmcalculates slopes associated with offset, interval pairs for each of theselected OCT scans. Thus, the algorithm generates sets of eight slopesfor each potential offset, interval pair. Correlating the sets of eightslopes to the eight measured blood glucose values, the algorithmgenerates a contour plot of Pearson's correlation coefficientscorresponding to the offset, interval pairs from the selected eight OCTscans and eight measured blood glucose levels to reduce the number ofpotential offset, interval pairs for calibrating the OCT-based bloodglucose monitor. Optionally, the algorithm may choose several OCT scanstemporally located near a measured blood glucose level and average theslopes of the OCT scans for each offset, interval pair. The algorithmthen uses the averaged slopes to compute the Pearson's correlationcoefficients. For example, the algorithm may select three OCT scanstemporally located around one measured blood glucose level and averagethe slopes of the three OCT scans to obtain an averaged slope value foreach offset, interval pair. The algorithm then computes Pearson'scorrelation coefficients using the averaged slope values and themeasured blood glucose level for multiple offset, interval pairs, andrepeats the process of using three OCT scans temporally located aroundeach measured blood glucose level.

By utilizing the Pearson's correlation method, the algorithm is able tomaximize the correlation between the OCT scan data and the measuredblood glucose levels and may choose an offset, interval pair and thecorresponding scattering coefficients, μ_(s), that closely imitate thevariations in the actual blood glucose levels (see, e.g., S306 of FIG.3B). For example, an algorithm may select one or more offset, intervalpairs with Pearson's correlation coefficients between about 0.8 andabout 1.0, and between about minus 0.8 (−0.8) and about minus 1.0(−1.0). If the algorithm wishes to narrow the correlated offset andinterval pairs, the algorithm may narrow the range of useful Pearson'scorrelation coefficients, such as, for example, to a range of about 0.9to about 1.0, and a range of about minus 0.9 (−0.9) to about minus 1.0(−1.0). As discussed above, high negative Pearson's correlationcoefficients represent a close correlation between the OCT scan data andthe measured blood glucose levels, but differ from positive Pearson'scorrelation coefficients in that the negative values represent that thechange in the slope of the OCT signal is decreasing as the change in theblood glucose level is increasing.

As shown in S307 of FIG. 3B, the algorithm selects an optimal offset,interval pair using the generated contour plot(s) and instructs thecomputer to generate a plot of the scattering coefficients correspondingto the selected offset, interval pair for all of the averaged OCT scanstaken during the testing time period, over the measured blood glucoselevels. FIG. 5 illustrates a plot of scattering coefficientscorresponding to one optimal offset, interval pair compared to measuredblood glucose levels. In FIG. 5, nineteen blood glucose measurementswere taken over a 190-minute time period, as shown by each black square.The rise and fall in the blood glucose line is due to the subjectingesting food during the 190-minute time period. Each circlecorresponds to a scattering coefficient, μ_(s), computed from the slopeassociated with the selected offset, interval pair, for an averaged OCTscan. In FIG. 5, scattering coefficients, μ_(s), corresponding to about125 averaged OCT scans, are represented by the circles. As shown in FIG.5, the scattering coefficients associated with the chosen offset,interval pair correlate closely (i.e., >95% confidence level) to themeasured blood glucose levels.

Accordingly, at S308 of FIG. 3B, the algorithm then uses the chosenoffset and interval and corresponding scattering coefficients, μ_(s), tocalibrate the OCT-based blood glucose monitor. To calibrate theOCT-based blood glucose monitor, estimated blood glucose levels arecalculated by taking the negative of the scattering coefficient valuesfor positively correlated scattering coefficients, μ_(s). Foranti-correlated scattering coefficients, estimated blood glucose levelsare calculated for the selected offset and interval pair.

While the present disclosure has been described with respect to what aresome embodiments of the disclosure, it is to be understood that thedisclosure is not limited to the disclosed embodiments. To the contrary,the disclosure is intended to cover various modifications and equivalentarrangements included within the spirit and scope of the appendedclaims. The scope of the following claims is to be accorded the broadestinterpretation so as to encompass all such modifications and equivalentstructures and functions.

1. A method for calibrating an optical coherence tomography (OCT) sensorby correlating OCT measurements with blood analyte measurements,comprising: receiving blood analyte measurements from a subject over aperiod of time; obtaining OCT measurements from biological tissue of thesubject using an OCT sensor such that at least one OCT measurement isassociated with each blood analyte measurement, each of the OCTmeasurements capable of being represented as a plot of intensity againstdepth of the biological tissue; selecting at least one portion of eachof the OCT measurements that includes a selected depth, the selectedportion of the OCT measurements correlating with the associated bloodanalyte measurements; and determining, using a processor, a calibrationrelationship for the OCT sensor using the selected portions of the OCTmeasurements and the associated blood analyte measurements.
 2. Themethod of claim 1, further comprising: using the calibrationrelationship to convert subsequent OCT measurements into estimated bloodanalyte concentrations.
 3. The method of claim 2, wherein the step ofobtaining OCT measurements comprises selecting a wavelength of light forwhich an absorption coefficient of the biological tissue is smallrelative to a scattering coefficient of the biological tissue.
 4. Themethod of claim 3, wherein the wavelength of light is within a range ofabout 770 nm to about 1400 nm.
 5. The method of claim 3, wherein thestep of obtaining OCT measurements further comprises scanning a twodimensional surface area of the biological tissue, andinterferometrically scanning in a depth dimension.
 6. The method ofclaim 5, wherein the step of scanning the two dimensional surface areafurther comprises averaging data from scanning the two dimensionalsurface area to obtain the at least one OCT measurement associated witheach blood analyte measurement.
 7. The method of claim 1, wherein thestep of receiving blood analyte measurements from a subject over aperiod of time comprises receiving at least two blood analytemeasurements that differ in concentration values by at least about 40mg/dL.
 8. The method of claim 1, wherein the step of selecting at leastone portion of each of the OCT measurements comprises: computingintensity differences between at least two of the obtained OCTmeasurements at corresponding depths to generate an intensity differenceplot, and using the intensity difference plot to obtain the selectedportion and the selected depth of the OCT measurements.
 9. The method ofclaim 8, wherein the step of using the intensity difference plotcomprises identifying regions of the OCT measurements that have largechanges in intensity.
 10. The method of claim 8, wherein the step ofusing the intensity difference plot comprises identifying regions whereintensity differences correlate with blood analyte level changes. 11.The method of claim 8, wherein the step of using the intensitydifference plot comprises identifying regions where intensitydifferences correlate with blood vessels.
 12. The method of claim 8,wherein the step of using the intensity difference plot comprises usingdata of the intensity difference plot corresponding to thepeak-to-valley pattern to obtain the selected portion and the selecteddepth of the OCT measurements.
 13. The method of claim 8, wherein thestep of using the intensity difference plot comprises identifying amultitude of selected portions and selected depths for the OCTmeasurements.
 14. The method of claim 13, wherein the step ofidentifying the multitude of selected portions and selected depthscomprises constructing a analyte vector grid, an entry of the analytevector grid being associated with a measure of a change in a slopebetween two OCT measurements at one selected portion and one selecteddepth
 15. The method of claim 1, wherein the step of selecting at leastone portion of each of the OCT measurements comprises: enhancing atleast one discontinuity in data associated with an obtained OCTmeasurement; and using the at least one discontinuity to identify theselected depth.
 16. The method of claim 15, wherein the step ofenhancing at least one discontinuity comprises generating a secondderivative plot from the obtained OCT measurement.
 17. The method ofclaim 15, wherein the at least one discontinuity correlates closely witha location of a tissue interface transition.
 18. The method of claim 17,wherein the tissue interface transition is a blood vessel.
 19. Themethod of claim 15, wherein the at least one discontinuity correspondsto changes in blood analyte levels.
 20. The method of claim 15, furthercomprising: constructing a analyte vector grid using at least oneidentified selected depth.
 21. The method of claim 1, wherein the stepof selecting at least one portion of each of the OCT measurementscomprises: creating a Pearson plot to indicate correlations between aplurality of OCT measurements at a plurality of portions and depths ofthe OCT measurements; and using the Pearson plot to select the at leastone portion of the OCT measurements and the selected depth.
 22. Aphysiological monitoring system for determining a blood analyte levelusing an optical coherence tomography (OCT) sensor comprising: anon-invasive OCT sensor configured to: scan an area of biological tissueand interferometrically scan in a depth dimension during a period oftime; and generate one or more OCT measurements based on the scanning;and a physiological monitor comprising at least one processor, thephysiological monitor configured to: receive the one or more OCTmeasurements; select one or more portions of the one or more OCTmeasurements corresponding to a predetermined depth; and determine anestimated blood analyte level in the biological tissue based on acomparison of the one or more selected portions of the OCT measurementscorresponding to the predetermined depth to one or more OCT calibrationcurves.
 23. The system of claim 22, wherein the predetermined depth isdetermined by: computing intensity differences between at least two OCTmeasurements at corresponding depths to generate an intensity differenceplot; and selecting a depth from the intensity difference plotcomprising a region having a large change in intensity.
 24. The systemof claim 22, wherein the predetermined depth is determined by: enhancingat least one discontinuity in data associated with an obtained OCTmeasurement; and using the at least one discontinuity to identify thepredetermined depth;
 25. The system of claim 22, wherein thepredetermined depth is determined by: creating a Pearson plot toindicate correlations between a plurality of OCT measurements at aplurality of portions and depths of the OCT measurements; and using thePearson plot to select the predetermined depth.